Introduction VOLIBRIS 5 mg film-coated tablets B/30 (CIP code: 386 578-1) VOLIBRIS 10 mg film-coated tablets B/30 (CIP code: 386 580-6) Posted on Jan 05 2011 Active substance (DCI) ambrisentan Pneumologie - Mise au point Progrès thérapeutique :– important pour FLOLAN ;– modéré pour TRACLEER ;– mineur pour ADCIRCA, REMODULIN, REVATIO, VENTAVIS et VOLIBRIS Les médicaments de l’hypertension artérielle pulmonaire (HTAP) n'apportent qu'un bénéfice symptomatique, et celui-ci est modeste.FLOLAN (époprosténol) est le seul ayant montré une augmentation de la survie. Son rapport efficacité/effets indésirables est donc important ; il est modéré pour les autres médicaments.Il s’agit de médicaments de première intention, excepté REMODULIN et VENTAVIS, qui sont utilisés en deuxième intention.N.B. – THELIN a été retiré du marché en raison de son risque d'atteinte hépatique sévère.Pour en savoir plus, téléchargez la synthèse ou l'avis complet ci-dessous ATC Code C02KX02 Laboratory / Manufacturer GLAXOSMITHKLINE VOLIBRIS 5 mg film-coated tablets B/30 (CIP code: 386 578-1) VOLIBRIS 10 mg film-coated tablets B/30 (CIP code: 386 580-6) Posted on Jan 05 2011
Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
BACKGROUND AND INTRODUCTION The transparency Committee (TC) of HAS assesses medicinal products that have obtained a marketing authorisation when the company marketing them wishes them to be entered into the list of medicines refundable by National Health Insurance (articles L.162-17 of the Social Security Code and L.5123-2 of the Public Health Code) or on request. The TC is a scientific body comprised of medical practitioners, pharmacists and specialists in methodology and epidemiology. Its objectives are: to provide an opinion to the ministers responsible for health and social security concerning · the validity of the management of medicinal products by social security and/or of their use in hospital, notably with respect to their actual benefit (AB) as well as the improvement in actual benefit (IAB) they are likely to provide in comparison with the treatments that are already available; ·to contribute to the proper use of medicinal products by publishing relevant, independent scientific information concerning the products. These objectives are defined in the Social Security Code, in particular in articles R.163-2 to R.163-21, L.161-37, L.161-39 and L.161-41. According to articles L. 162-17, L. 161-37, L.161-39, L. 161-41, L. 161-44, R. 163-2 to R. 163-21, R. 161-71, R. 161-76, R. 161-85 of the Social Security Code and articles L. 5123-2 and L. 5123-3 of the Public Health Code, the TC's opinion specifies the actual benefit and improvement in actual benefit provided by the medicinal product. This assessment is performed on the basis of a critical analysis of the scientific literature, on the basis ofEvidence Based Medicine the opinion of and experts, with respect to the indications and dosages cited in the marketing authorisation. I. Objective of the transparency Committee initiative In accordance with article R-163-21 of the Social Security Code, the transparency Committee is acting on its own initiative to provide an opinion of the efficacy and tolerance of these medicinal products, in the light of the new proprietary products that have been developed for the treatment of pulmonary arterial hypertension (PAH), recent data from the literature and the dossiers submitted by the manufacturers concerned. II. General description The list of proprietary products included in the assessment is presented in Table 1. The indications, results of studies available during the inclusion process and the levels of AB and IAB assigned by the transparency Committee have been specified there (see Table 2 in Appendix 1 for the dosages and principal warnings and precautions for use).
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Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
II.1 Endothelin antagonists TRACLEER 62.5 mg, film-coated tablet B/56 (CIP code: 563 621-1) TRACLEER 125 mg, film-coated tablet B/56 (CIP code: 563 622-8) TRACLEER 32 mg, dispersible tablets B/56 (CIP code: 399 351-0) Applicant: ACTELION PHARMACEUTICALS FRANCE bosentan Date of European Marketing Authorisation (centralised): 15 May 2002 List I Medicine for hospital prescription only. Prescription restricted to specialists and/or hospital departments specialising in respiratory medicine, cardiology, rheumatology, dermatology, or internal medicine. Medicine requiring special monitoring during treatment. Orphan medicinal product (initial date of designation for TRACLEER proprietary products: 14 February 2001) THELIN 100 mg, coated tablets B/28 (CIP code: 379 171-7) Applicant: PFIZER sitaxentan Date of Marketing Authorisation (centralised procedure): 10 August 2006 Orphan medicinal product (date of designation: 21 October 2004) List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in cardiology, respiratory medicine or internal medicine. Medicine requiring special monitoring during treatment. VOLIBRIS 5 mg, film-coated tablets B/30 (CIP code: 386 578-1) VOLIBRIS 10 mg, film-coated tablets B/30 (CIP code: 386 580-6) Applicant: GSK (GlaxoSmithKline) ambrisentan Date of Marketing Authorisation (centralised procedure): 21 April 2008 Orphan medicinal product (date of designation: 11 April 2005) List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine, cardiology or internal medicine. Medicine requiring special monitoring during treatment. ATC Code (2010): C: Cardiovascular system C02: Antihypertensives C02K: Other antihypertensives C02KX: Other antihypertensives C02KX01: bosentan C02KX02: ambrisentan C02KX03: sitaxentan
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Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
II.2 Phosphodiesterase inhibitors REVATIO 20 mg, film-coated tablets B/90 (CIP code: 370 240-6) Applicant: PFIZER sildenafil Date of Marketing Authorisation (centralised procedure): 28 October 2005 Orphan medicinal product (date of designation: 12 December 2003 for sildenafil in the treatment of PAH). List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine, cardiology or internal medicine. ADCIRCA 20 mg, film-coated tablets B/28 (CIP code: 347 152-7) B/56 (CIP code: 347 153-3) Applicant: LILLY FRANCE tadalafil Date of Marketing Authorisation (centralised procedure): 30 November 2009 List I Medicine for hospital prescription only, restricted to specialists and/or departments specialising in pneumology, cardiology or internal medicine. ATC Code (2010): G: Genitourinary system and sex hormones G04: Urologicals G04B: Other urologicals, including antispasmodics G04BE: Drugs used in erectile dysfunction G04BE03: sildenafil G04BE08: tadalafilII.3 Prostacyclins FLOLAN 0.5 mg, powder and solvent for solution for injection 1 vial of 50 ml (CI code: 561 400-8) FLOLAN 1.5 mg, powder and solvent for solution for injection 1 vial of 50 ml (CIP code: 561 398-3) Applicant: GSK (GlaxoSmithKline) epoprostenol sodium Date of Marketing Authorisation (national procedure): 06 March 1998 List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine or cardiology. VENTAVIS 10 micrograms/ml, nebuliser solution B/ 30 ampoules each of 1 ml (CIP: 375 480-5) B/30 ampoules each of 2 ml (CIP: 564 920-2) Applicant: BAYER SANTE iloprost
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Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
Date of Marketing Authorisation for 2 ml ampoules (centralised procedure): 16 September 2003 Date of Marketing Authorisation for 1 ml ampoules (centralised procedure): 02 May 2006 Marketing authorisation granted under exceptional circumstances. The results of an observational study, which was requested by the CHMP (Committee for Human Medicinal Products) and which aims to collect data on long-term efficacy and tolerance, are expected in the 4th quarter of 2012. Orphan medicinal product (date of designation: 29 December 2000) List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine or cardiology. REMODULIN 1 mg/ml, solution for infusion (subcutaneous route) 1 glass vial of 20 ml (CIP code: 368 161-5) REMODULIN 2.5 mg/ml, solution for infusion (subcutaneous route) 1 glass vial of 20 ml (CIP code: 368 162-1) REMODULIN 5 mg/ml, solution for infusion (subcutaneous route) 1 glass vial of 20 ml (CIP code: 368 163-8) REMODULIN 10 mg/ml, solution for infusion (subcutaneous route) 1 glass vial of 20 ml (CIP code: 368 164-4) Applicant: BIOPROJET PHARMA treprostinil sodium Date of Marketing Authorisation (mutual recognition procedure): 28 February 2005 List I Medicine for hospital prescription only, with prescription restricted to specialists and/or hospital departments specialising in respiratory medicine or cardiology. ATC Code (2010): B : Blood and blood-forming organs B01 : Antithrombotic agents B01A : Antithrombotic agents B01AC: Inhibitors of platelet aggregation, excluding heparin B01AC09: epoprostenol B01AC11: iloprost B01AC21: treprostinil
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Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
Table 1: ProrpordietcatryRIoNuNteofonIn(diDcaatteioonfimnamrkaertkientginagutahuotrhisoraitisoatni)onp u administrati Medicinal products in the same therapeutic category Endothelin antagonists:
TRACLEER62.5 mg and 125 mg
TRACLEER62.5 mg and 125 mg
Bosentan Oral route
Bosentan Oral route
Treatment of PAH to improve exercise capacity and symptoms in patients in functional class III. Efficacy was demonstrated in primary PAH and in PAH secondary to scleroderma without significant associated interstitial disease. (date of marketing authorisation: 15 May 2002) Included on the list of medicines approved for hospital use since 19 March 2003
Treatment of pulmonary arterial hypertension associated with left-to-right shunt congenital heart disease with Eisenmenger syndrome. (date of marketing authorisation: 27 October 2006)
Results of studies supplied to the Committee concerning the primary efficacy endpoint: distance walked in 6 minutes
- in a study in 32 subjects with stage III primary PAH (and 4 subjects with PAH secondary to scleroderma), a significant improvement was observed in the distance walked in 6 minutes: gain around 51 m for patients treated with bosentan 125 mg x2/day after 12 weeks of treatment compared to those receiving placebo. - in the BREATHE-1 study in 213 subjects, of whom 150 had primary PAH and 47 PAH secondary to scleroderma, a significant improvement was observed in the distance walked in 6 minutes: gain of the order of 44 m for patients treated with bosentan after 16 weeks of treatment compared to those receiving placebo. The efficacy and tolerance of TRACLEER were evaluated in patients with functional class III pulmonary arterial hypertension associated with left-to-right shunt congenital heart disease with Eisenmenger syndrome in a comparative, placebo-controlled, randomised, double-blind study in 54 patients (37 in the TRACLEER group, 17 in the placebo group). In this study, it was planned to analyse 2 endpoints: a comparison between TRACLEER and placebo of the change in transcutaneous oxygen saturation determined between the start and end of treatment according to a hypothesis of non-inferiority; a comparison between TRACLEER and placebo of the change in pulmonary vascular resistance determined between the start and end of treatment according to a hypothesis of superiority. The non-inferiority of TRACLEER with respect to placebo having been previously demonstrated for the criterion "change in transcutaneous oxygen saturation", a statistically significant decrease in pulmonary
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Conclusions of the Committee (AB, IAB, Date of the opinion)
Opinion of the TC of 5 February 2003: Substantial AB TRACLEER has the same IAB as FLOLAN (IAB I) in patients with primary PAH or PAH secondary to scleroderma. Its administration by the oral route is a significant advantage
Opinion of the TC of 18 July 2007: Substantial AB TRACLEER provides a moderate improvement in actual benefit (IAB III) in the management of pulmonary arterial hypertension associated with left-to-right shunt congenital heart disease with Eisenmenger syndrome.
Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
INNInd PrporpordieutcatryRouteof(iDcaatteioonfimnamrkaertkientginagutahuthiosraitsiaotni)onRceosunlctesrdonifisnstgatuntdhcieeespwrsailumkpaeprdlyiieendff6itcomatichnyeuteCenosdmpomiinttt:ee(CAoBn,cIluAsBi,oDnsatoefotfhtehCeoompimniitotne)e administration or vascular resistance was observed for TRACLEER and placebo between the start and the end of treatment (decrease of 472.01 dyne.sec.cm-5). However, this decrease was moderate and related to an intermediate endpoint. Opinion of the TC of 21 January 2009: The actual benefit is considered to be substantial, pending reassessment of all therapies for TheefficacyandtoleranceofbosentaninpatientsCPoAmHmittebeythetransparencywith PAH in functional class II were evaluated in IAB: . the EARLY phase III, placebo-controlled, Some improvements were also demonstrated in randomised, double-blind study conducted in 185 On the basis of the available clinical patientswihtehWpuHlOmoInIafryuncatirotenrailalclahsyspe(rtdeantesioonfpatientswithPAH.data,theCommitteewasnotableto16T22R.55AmCmLgEgEaRndOBroaslernotuatne(ePxtAeHn)sioinnotfindication:29July2008)1A9ft.e1rm6obmsoenrtvhesdoifntcroeamtpmaerinst,onthteopdlifafceerebnocewitohfpTqauRtaiAenCtnitfLsyEEowRnitthihnientphfuuelncmcomtoniatonrnniaabarluygteicomlnaaerstnsetriIoIao.flf respe t to the criterion "distance covered in the 6- hypertensi c minute walking test" was not statisticall Included on the list of medicines approved for y hospitalusesince21October2008tshigannifitchaent.thFruersthhoelrdmoorfe,3t5hismdiffceornesnicdeerwedastloowbeertTdhheeersefonroettrpacrnoosnvpsiidadreeeranscntyhimatprToCRvoAemCmLmeiEntttEeiRneclinicallyrelevant.aoctualbenefit(IABV)inthe ent of idiopathi managem c pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or congenital heart disease in patients in functional class II. Treatment of pulmonary arterial hypertension The FUTURE-1 pharmacokinetics study Opinion of the TC of 10 February (PAH) to improve exercise capacity a1ithopdihiatorcllcaevypesficiTwiesh1a0r:y0e221to2fpimttoyrmbfsendoeemugaalneasrcndtdlchin36mgi32ELRERTCAetdlaau is considered to TRACLEER Bosentan in patients in WHO functional class III . be substantial, pending 32mgOralrouteEfficacyh-aspbreiemnarsyhow(indiion:pathicandfamilial)fTahmeirliealaPrAeHnooffeufnficctiaocnyalsctluadsisesIIoarvIaIiIl.able,whichreassessmentofalltherapiesforpulmonary arterial hypertension; have been conducted specifically in children, PAH by the transparency - pulmonary arterial hypertension particularly those with PAH associated with Committee. 1pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43: S40-S47. The NYHA classification (New YorkBarst RJ et al. Diagnosis and differential assessment of Heart Association Functional Classification) is based on the functional capacity of the patient. It divides patients into 4 classes: - Class I : no limitation of physical activities. No dyspnoea and no fatigue during everyday activities - Class II : moderate limitation of physical activities. Discomfort during strenuous physical activities. No discomfort at rest. - Class III : marked limitation of physical activities. Discomfort during even moderate everyday activities. No discomfort at rest. - Class IV : unable to undertake most everyday activities without considerable discomfort. Discomfort at rest.
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Proprietaryproduct
THELIN
VOLIBRIS
INN Route of administration
Sitaxentan Oral route
AmbrisentanOral route
Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
Results of stud IndicationinmarketingauthorisationconcerningthieesprsiumpaprlyieedffitoatchyeeCnodmpomiinttt:ee(Dateofmarketingauthorisation)distancewalkedin6cminutessecondary to scleroderma without significant congenital heart disease, a very common associated interstitial disease; aetiology in children. pulmonary arterial hypertension -associated with left-to-right shunt congenital hea t r disease with Eisenmenger syndrome. Some improvements have also been shown in patients with pulmonary arterial hypertension (PAH) in WHO functional class II. TRACLEER is also indicated to reduce the number of new digital ulcers in patients with emic sclerosis and progressive digital ulcer dsiyssetase(Dateofmarketingauthorisation:1st July 2009). Included on the list of medicines approved for hospital use since 18 June 2010
Treatment of pulmonary arterial hypertension with the aim of improving the exercise capacity of patients in functional class III (WHO classification). The efficacy of the treatment was demonstrated for primary pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease. (date of marketing authorisation: 10 August 2006) Included on the list of medicines approved for hospital use since 10 August 2007
VOLIBRIS is indicated in the treatment of pulmonary arterial hypertension (PAH) in patients in functional classes II and III (WHO classification) in order to improve exercise capacity. Its efficacy has been demonstrated in idiopathic PAH and in PAH associated with systemic collagen tissue
- study FPH02: comparative, randomised, double-blind study in 247 patients with PAH. An improvement of 31.4 metres, which was statistically significant was observed in the 6-minute walking test (primary study endpoint, 95% CI [5.4; 57.4], p = 0.03). - study FPH04: phase III, comparative, randomised, double-blind study in 98 patients with PAH. The improvement in the walking distance with THELIN compared to placebo was 24.3 m. This difference was not statistically significant.The tolerance of ambrisentan and its efficacy with respect to exercise capacity in PAH patients in functional classes II and III were evaluated in two phase III, placebo-controlled, randomised double-blind comparative studies, 12 weeks in duration, which included a total of 393 patients with
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Conclusions of the Committee (AB, IAB, Date of the opinion)
IAB: In the absence of clinically relevant data, the transparency Committee is unable to quantify the contribution of TRACLEER 32 mg dispersible tablets in the management of patients with primary PAH or PAH associated with scleroderma or congenital heart disease in functional class II or III . It is a useful addition to the therapeutic battery for the management of PAH, particularly in children. TRACLEER 32 mg dispersible tablets do not provide an improvement in actual benefit (IAB V). Opinion of the TC of 20 June 2007: Substantial AB The Committee was not able to quantify the contribution of THELIN compared to existing treatments due to the absence of comparative studies with methodology of a good quality. The transparency Committee is therefore of the opinion that THELIN does not offer an improvement in actual benefit (IAB V) compared to the available proprietary products that are indicated in the treatment of primary pulmonary arterial hypertension and pulmonary arterial hypertension associated with connective tissue disease Opinion of the TC of 16 July 2008: The actual benefit is considered to be substantial, pending reassessment of all therapies for PAH by the transparency Committee.
Proprietaryproduct
INN Route of administration
Reassessment of the treatments for pulmonary arterial hypertension (PAH) - APPENDIX
Results of studies supplied to the Committee In(dDicaatteioofnimnarmkaertiknetginagutahuotrhisoraitisoatni)onconcerdniisntganthceepwrailmkaerdyienff6icmaicnyuteensdpoint:disease. (date of marketing authorisation: 21 April primarily idiopathic PAH or PAH associated with 2008) connective tissue disease. In each study, after 12 weeks of treatment, a Included on the list of medicines approved for statistically significant difference was observed in hospital use since 21 October 2008 favour of the ambrisentan treatment groups compared to the placebo group with respect to the primary efficacy endpoint of distance walked in the 6-minute walking test (improvement of 30.6 m in the 5 mg group and 51.4 m in the 10 mg group in the ARIES 1 study, and improvement of 59.4 m in the ARIES 2 study)
Medicines with a similar therapeutic aim Phosphodiesterase inhibitor: Treatment of PAH in patients in functional class III according to the WHO classification, in order to improve exercise capacity. Its efficacy has been REVATIO Sildenafil demonstrated in idiopathic PAH and in PAH keofmauttingalsritaohOir82eOuntoro:2erobct5)00widcthocssteiaa.(datediseaseeitsseunoentcvi ar Included on the list of medicines approved for
Phase III, placebo-controlled, randomised, double-blind study conducted in 277 subjects. After 12 weeks of treatment, the mean increase in walking distance over 6 minutes, compared to baseline and corrected with respect to placebo, was 45 metres (p <0.0001).
Conclusions of the Committee (AB, IAB, Date of the opinion)
The Committee was not able to quantify the contribution of VOLIBRIS compared to existing treatments due to the absence of comparative studies. The transparency Committee is therefore of the opinion that VOLIBRIS does not offer an improvement in actual benefit (IAB V) compared to the available proprietary products that are indicated in the treatment of idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with systemic collagen disease
Opinion of the TC of 15 February 2006: Substantial AB REVATIO offers the same IAB as TRACLEER1
hospital use since 12 April 2006 ADCIRCA is indicated in adults for the treatment The efficacy and tolerance of tadalafil (ADCIRCA) Opinion of the TC of 21 July 2010: of pulmonary arterial hypertension (PAH)2lacalonIIesssiHAPhtitcnufnsadlcsessaeIfIenIniaitdtuacbaleitnsiwnipttaeTh classified as WHO functional class II and III , o was evaluated in the LVGY placebo-controlled, moderate, pending reassessment of improve exercise capacity. randomised, double-blind, phase III study, which PAH therapies. ADCIRCATadalafilaEnffidciancyPAhaHsrebleaetendsthoocwonlliangiedniovpaastchiuclaPrAdH(IPAH)included406patientswithPAH(82intheplaceboIAB:Oral route isease. group, 79 in the group receiving tadalafil 40 mg, The Committee was not able to (date of marketing authorisation: 30 November the recommended dosage in the Marketing quantify the contribution of the 2009) Authorisation). proprietary product ADCIRCA compared to existing treatments due After16 weeks of treatment, the difference of 26.0 to the absence of comparative 2the patient. It divides patients into 4 classes:The NYHA classification (New York Heart Association Functional Classification) is based on the functional capacity of - Class I : no limitation of physical activities. No dyspnoea and no fatigue during everyday activities - Class II : moderate limitation of physical activities. Discomfort during strenuous physical activities. No discomfort at rest. - Class III : marked limitation of physical activities. Discomfort during even moderate everyday activities. No discomfort at rest. - Class IV : unable to undertake most everyday activities without considerable discomfort. Discomfort at rest.